ABSTRACT/SUMMARY Small cell lung cancer (SCLC) is one of the few malignancies with such poor outcomes that it meets the definition of a ?recalcitrant? cancer, accounting for 30,000 American lives each year with five-year survival rates of just ~7%. Somewhat lost in these dismal statistics is the fact that patients diagnosed early (limited stage) display vastly superior survival metrics when compared to those diagnosed late (extensive stage). Unfortunately, only a minority of cases are identified at limited stage, and the computed tomography (CT) screening approaches capable of early detection for non-small cell lung cancer (NSCLC) have not proven effective for SCLC. We will employ a novel two-mode, array based, hybrid plasma marker methodology capable of detecting autoantibody- autoantigen complex and unbound autoantibody markers for SCLC early detection. One of the major problems with studying SCLC is there are few studies and cohorts that have appropriate plasma samples. We have accumulated robust biomarker candidates centered around autoantibody-antigen complexes using the Cardiovascular Health Study (prediagnostic), Fred Hutch Lung Cancer Early Detection and Prevention Clinic, and Vanderbilt SCLC sample sets and will comprehensively define free autoantibodies levels in these same cohorts. We propose to test a fixed combination rule combining both autoantibody approaches using all of the prediagnostic SCLC samples from the Women's Health Initiative (WHI), the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO), and the National Lung Screening Trial (NLST) cohorts and diagnostic samples from Moffitt Cancer Center. Using prediagnostic samples allows us to effectively model early detection much more accurately than after diagnosis occurs, and this is particularly important for SCLC as diagnosis at the extensive stage is nearly almost always fatal. Part of our analysis will determine how early our autoantibody marker panel can predict the presence of SCLC and whether a tumor can be observed via CT at that time in order to evaluate the timing and implementation of our early-detection procedure.